Pain continues to be a primary concern and a major complication in patients suffering from advanced cancer. Despite improvements in medication, delivery systems and physician awareness, a significant population of cancer patients continue to experience severe, intractable pain. Alternative treatment addressing severe pain would substantially reduce the suffering and improve the quality of life of these patients. This study proposes a novel approach to managing severe chronic pain. The hypothesis to be tested is that over-expression of opioid receptors in the dorsal horn of the primary afferents will produce profound analgesia while reducing drug requirements for pain relief. Native opioid receptors will be over-expressed using replication defective adenovirus to confer increased drug sensitivity to the synapse of the primary pain fibers in the spinal cord. Lower doses of drug are needed to obtain effective analgesia, thereby decreasing opioid requirements and systemic untoward effects. The results of this study will demonstrate the feasibility of this approach to pain therapy in rat pain models and provide the basis for future clinical trials. Dr. Mannes, an Assistant Professor of Anesthesiology at the University of Pennsylvania Medical Center, is applying for a Clinical Investigator Award to pursue an academic career focusing on gene therapy to alleviate severe pain. He has a long-standing interest in treating pain including his fellowship in pain management and current clinical experience. This application requests support to allow him to undertake a comprehensive career development program including: 1) further course work in molecular biology, gene therapy, virology, immunology and neuroanatomy; 2) a research preceptorship with Michael Iadarola, Ph.D., extensive consultation with James Wilson, Director of the Institute for Human Gene Therapy, and John Farrar, MD; and 3) a research project that will provide him with the skills and experience to pursue a successful career as an independent investigator.